Programmed DNA Rearrangements During Differentiation: Immunoglobulin Class Switching

Year: 1981 DOI: 10.7907/KFJS-G857 The events of B-lymphocyte differentiation can be reconstructed in part through an analysis of the organization of heavy-chain genes isolated from B-cell tumors (myelomas). A mouse immunoglobulin alpha heavy-chain gene is shown to be composed of at least three non-contiguous segments of germline DNA -- a VH gene segment, a JH gene segment adjacent to the Cμ coding region, and a Cα gene segment. These gene segments are joined together by two distinct types of DNA rearrangements: variable region formation and immunoglobulin class switching. Three examples of IgM → IgA elass switching were examined and in each case a different site adjacent to Cμ and a different site adjacent to Cα were joined together in the process of switching. Two of the three Cμ sites shared significant homology to each other (15/25 nucleotides) and all three of Cα sites were highly homologous (22/30 nucleotides). We believe these sequences serve as recognition sites for class switching. Furthermore, the lack of homology between the Cα consensus sequence and sequences reported for Cγ1 and cγ2b recombination sites suggests that this process is mediated by class-specific recognition sequences and, presumably, class-specific regulatory mechanisms. A number of predictions and possible explanations of immune phenomena result from this observation. Apparently nonproductive DNA rearrangements, occurring in the same tumor lines, seem also to utilize some of the _same regulatory apparati. In addition, it appears that in one example, MClOl, class switching has progressed from Cμ → Cα → Cγ1. This switching pathway presents difficulties for the simple deletional model of CH switching.